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Ferric Chloride-induced Murine Thrombosis Models
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A high affinity, antidote-controllable prothrombin and thrombin-binding RNA aptamer inhibits thrombin generation and
K M Bompiani1, D M Monroe, F C Church
1Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Journal of Thrombosis and Haemostasis : JTH
|March 6, 2012
Summary
A novel RNA aptamer, RNA(R9D-14T), effectively inhibits thrombin activity and coagulation. Its anticoagulant effects can be rapidly reversed by an antidote, suggesting potential clinical applications for anticoagulation therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Thrombin is a key enzyme in blood coagulation, making it an attractive target for anticoagulants.
- Existing antithrombin therapies pose bleeding risks, necessitating safer alternatives.
- A modified RNA aptamer, R9D-14, was previously identified as a potent in vitro anticoagulant targeting prothrombin.
Purpose of the Study:
- To investigate the structure and anticoagulant mechanisms of R9D-14.
- To develop an optimized aptamer, RNA(R9D-14T).
- To assess the ability of complementary oligonucleotides to reverse the anticoagulant activity of RNA(R9D-14T).
Main Methods:
- High-affinity binding assays for RNA(R9D-14T) to prothrombin and thrombin.
- In vitro assays measuring thrombin generation and thrombin exosite I-mediated activities.
- Clotting assays including activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin clotting time (TCT).
- Evaluation of antidote oligonucleotide efficacy in reversing anticoagulation.
Main Results:
- RNA(R9D-14T) demonstrated high-affinity binding to prothrombin and thrombin's exosite I.
- The aptamer potently inhibited thrombin generation and exosite I-mediated functions, including fibrin clot formation, feedback activation, and platelet activation.
- RNA(R9D-14T) significantly prolonged clotting times in aPTT, PT, and TCT assays, outperforming the DNA aptamer ARC-183.
- A complementary antidote rapidly (<2 min) and durably (>2 h) reversed RNA(R9D-14T)-induced anticoagulation in vitro.
Conclusions:
- RNA(R9D-14T) exhibits potent anticoagulation properties.
- The rapid and durable reversibility of RNA(R9D-14T) by an antidote is a significant advantage.
- RNA(R9D-14T) holds promise for clinical use in situations demanding rapid and robust anticoagulation, such as cardiopulmonary bypass, deep vein thrombosis, stroke, and percutaneous coronary intervention.
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